Higher throughput experimentation is a consistent goal for high-technology industries that depend upon research and development for growth, e.g., pharmaceutical, biotechnology and chemical industries. In the case of biological and chemical research, microfluidic technology has attempted to address this need by miniaturizing, automating and multiplexing experiments so that more experiments can be carried out faster and in a less expensive fashion. However, even these advances have highlighted the need and/or desire for even higher throughput experimentation within these industries. In particular, as with every other type of fluid based experimentation, microfluidic technology is limited by the fact that analyzing a given reaction requires mixing the reagents together in isolation and analyzing the results. Typically, such analysis has required a separate reaction vessel into which the different reagents must be pipetted. Higher throughput has then been achieved by increasing the number of reaction vessels, e.g., through the use of multiwell plate formats, increasing the complexity of pipetting systems, or in some rare cases, by carrying out multiple reactions in a single mixture. As can be readily appreciated, when one wishes to perform a matrixed experiment, e.g., testing each of a first library of reagents against each of a second library of experiments, the number of different reactions can potentially be staggering.
One example of such a matrixed experiment that is of considerable interest is that involved in genotyping experiments, e.g., SNP genotyping. In particular, it has been hypothesized that there is a correlation between the genetic footprint of a patient, e.g., as represented by the pattern of different genetic markers, e.g., SNPs, and that patient's response to different pharmaceutical treatments, susceptibility to disease, etc. In order to identify such a pattern, a large number of different patients need to be genotyped as to a large number of different genetic marker loci, in order to identify such correlations, so that they can be later used as diagnostic or therapeutic aids.
Microfluidic systems have addressed the throughput need for analytical operations, including genetic analysis, by providing very small fluidic channels coupled to an external fluid sipping element, e.g., a sampling capillary, through which reagents are drawn into the fluidic channel, where different reactions are carried out (See commonly owned U.S. Pat. No. 5,942,443). By serially drawing different samples into flowing reagent streams, such systems are capable of analyzing large numbers of different reactions in a relatively short amount of time. Further, by providing multiple parallel sipping and channel systems, one can further increase the number of experiments that are carried out.
While these systems have proven highly effective, each channel network has typically only been used to perform a single assay against a battery of test compounds or reagents. For example, in a particular channel, a given enzyme or target system is screened against a large number of potential inhibitors or test compounds. In the case of a matrixed experiment, e.g., screening a large number of enzymes or targets against a large number of potential inhibitors or test compounds, this particular operation would amount to one column of the matrix. Different columns of the matrix would be performed by other channel systems that are either within the same body or device, or are alternatively, completely separate. For example, one channel may be used to screen compounds for an effect on one enzyme system, while another channel in the same device, would be used to screen those compounds for an effect on a different enzyme system.
By way of example, in previously described operations, a first reagent is resident within the microfluidic device and is continuously introduced into the channels of the device. A large number of different second reagents are then serially introduced into the channel system to be reacted with (or interrogated against) the first reagent. Other reaction channel networks in the same device then optionally include different first reagents to perform other columns of the matrix. However, complexities of fixed sampling element positioning in microfluidic devices make such experiments difficult to configure, as different channel systems would not visit all of the same external sample sources, e.g., certain channels would not be able to access all of the test sample wells in a multiwell plate.
The present invention addresses the needs of higher throughput, matrixed experimentation, while taking advantage of the benefits of microfluidic technology in miniaturization, integration and automation.